Vertex to develop conditioning agent for SCD gene-editing therapy

Vertex, CRISPR are seeking exa-cel's approval in the US

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Vertex Pharmaceuticals will use ImmunoGen technology to develop less aggressive conditioning approaches for exagamglogene autotemcel (exa-cel), its experimental gene-editing therapy for sickle cell disease (SCD) and transfusion-dependent beta thalassemia.

Vertex will pay ImmunoGen $15 million up front to use its antibody-drug conjugate (ADC) technology to develop gentler and more targeted conditioning agents.

Chemotherapy, a type of conditioning agent, is used to wipe out a person’s faulty cells before gene-editing therapy is used. It’s known to be aggressive and poorly tolerated, though.

While Vertex will be able to obtain worldwide exclusive rights to develop and commercialize any products developed during an initial research phase, ImmunoGen may be entitled to up to $337 million, based on certain development and commercial milestones. If any product is approved, it will also earn royalties.

“We look forward to evaluating the potential of ImmunoGen’s technology to develop a gentler conditioning regimen for use with Vertex’s exagamglogene autotemcel (exa-cel), for the potential treatment of sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT),” Mike Cooke, PhD, senior vice president of Vertex Cell and Genetic Therapies, said in a company press release.

Vertex and its development partner, CRISPR Therapeutics, have opened a rolling submission with the U.S. Food and Drug Administration (FDA) for exa-cel’s approval in the U.S. That application is expected to be complete this year.

The treatment holds fast track, regenerative medicine advanced therapy (RMAT), and orphan drug designations in the U.S., all of which offer regulatory support and financial incentives for its development.

Regulatory submissions have also been made in the U.K. and EU, where the treatment holds orphan drug status. It also holds a priority medicines designation in the E.U.

A feature of SCD is the production of a faulty version of hemoglobin, the protein in red blood cells responsible for oxygen transport. Beta thalassemia patients have low hemoglobin or lack it altogether. Patients have anemia, wherein there isn’t enough healthy red blood cells to carry oxygen through the body.

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Hows does exa-cell gene editing work?

Formerly known as CTX001, exa-cel involves genetically modifying a patient’s hematopoietic stem cells (blood cell precursors) to make high levels of fetal hemoglobin, a version of the protein produced during fetal development that switches to an adult version after birth. Fetal hemoglobin is more effective than its adult counterpart at carrying oxygen.

Edited stem cells are transplanted back into the patient via a stem cell transplant, where they’re expected to populate blood with cells that produce high levels of fetal hemoglobin, which can ease anemia.

In clinical trials, patients have been treated with the chemotherapy agent busulfan before receiving the edited cells, but busulfan is aggressive and often poorly tolerated.

ImmunoGen has been working on ADCs to offer a more targeted approach for cancer patients. ADCs are made by attaching a potent cancer-killing agent to an antibody that will specifically recognize cancer cells. This approach is expected to help improve treatment tolerability because only cancer cells are targeted.

Vertex will use that technology to develop targeted conditioning agents for SCD and beta-thalassemia patients undergoing exa-cel treatment.

“Given Vertex’s extensive experience discovering and developing transformative medicines for patients with serious diseases, we are thrilled they have chosen to explore ImmunoGen’s technology to develop ADCs for transplant conditioning in connection with gene editing,” said Michael Vasconcelles, MD, ImmunoGen’s executive vice president of research, development, and medical affairs.

Data from an ongoing open-label Phase 2/3 clinical trial called CLIMB–121 (NCT03745287)  showed a single dose of exa-cel boosted fetal hemoglobin and prevented painful vaso-occlusive crises in patients with severe SCD, ages 12-35.

Reported side effects were consistent with those known to be associated with busulfan.

A pair of open-label Phase 3 trials — CLIMB–151 (NCT05329649) and CLIMB–141 (NCT05356195) — are evaluating the safety and effectiveness of exa-cel in pediatric patients, ages 2-11, with severe SCD or beta-thalassemia. CLIMB-151 is recruiting at sites in the U.S. and Italy. CLIMB-141 is recruiting in Canada, Germany, and the U.K.

Participants in any of these trials can enroll in CLIMB-131 (NCT04208529), where the treatment’s safety and effectiveness will be monitored for up to 15 years.